The present invention relates to electrochemical sensors, particularly to sensors for detecting urea in body fluids, and more particularly to a sensor capable of detecting and quantifying urea in fluids resulting from hemodialysis procedures.
There are currently more than 300,000 people with end-stage renal disease in the United States who require regular hemodialysis. Urea is generally accepted to be the best marker for evaluating the level of uremic toxins. Dialysis procedures are therefore aimed at reduction of urea in the blood stream. Currently, most dialysis clinics use the simple index of time of dialysis to determine the adequacy of dialysis. Blood draws (or other methods of obtaining blood samples) to accurately measure the level of urea in blood are often done infrequently to lower cost. The frequency of this measurement, which requires the use of clinical laboratories, varies from facility to facility. Turnaround time for these samples can be quite long, and often the patient must be recalled for further dialysis if the percentage reduction of urea in the blood is not sufficient. In the absence of a blood check, the use of time of dialysis alone as a measure of completion, especially if hemodialysis is not carried out long enough, can clearly lead to morbidity and mortality.
Substantial effort has been directed toward development of procedures for dialysis and blood urea monitoring, and various mechanical and sensor systems and methods have been developed, as exemplified by various patents including International Patent WO94/08641, April 1994, to P. Keshaviah et al.; European Patent EP504772, November 1992, to B. Skerratt; and U.S. Pat. No. 4,452,682 issued June 1984 to Y. N. Takata et al.; No. 3,930,957 issued January 1976 to J. P. Cummings et al.; No. 4,225,410 issued September 1980 to S. J. Pace; No. 5,308,315 issued May 1994 to R. N. Khuri et al.; and No. 4,244,787 issued January 1981 to E. Klein et al. In addition, a sensor has been recently developed which deals with dialysis monitoring, as described and claimed in copending U.S. application Ser. No. 08/517,011, filed Aug. 18, 1995, entitled "Chemiresistor Urea Sensor", and assigned to the same assignee.
Also, there is substantial published literature on urea sensors which deal with the use of a glass pH electrode (conventional liquid-filled glass tube), see R. Tor et al., Anal. Chem. 58, 1042-1046 (1986); R. Koncki et al., Anal. Chim. Acta. 257, 67-72 (1992); and P. Pietta et al., Ann. NY Acad. Sci., Vol. 672, 257 (1992). Also, publications have dealt with the use of metal/metal oxide systems as a basis for measurement of pH changes to determine urea concentration in various fluids, see N. Szuminsky et al., Biotech. and Bioeng., Vol. XXXVI, 642-645 (1984); R. Iannielo et al., Anal. Chim. Acta., 146, 249-252 (1983); M. Przybyt et al., Anal. Chim. Acta., 239, 269-276 (1990); and M. Przybyt et al., Anal. Chim. Acta., 237, 399-404 (1990). The above-referenced Ianniello et al. article in particular deals with the use of iridium oxide as a pH-sensitive material.
All of these prior devices rely upon the encapsulation of the enzyme urease, which catalyzes the hydrolysis of urea to yield products which result in the pH changes, which are then detected and related to the original urea concentration in the monitored fluid. Encapsulation using bovine serum albumin, cross-linked using glutaraldehyde has been previously discussed (e.g. above-reference N. Szuminsky et al., article).
Thin film deposition for sensor fabrication has been previously utilized for environmental sensors, see U.S. Pat. No. 5,120,421 issued Jun. 9, 1992; and No. 5,296,125 issued Mar. 22, 1994, each in the name of R. S. Glass et al.
It has long been desired to have a sensor which could monitor the progress of the dialysis procedure in "real-time", thereby assuring that the procedure was complete and obviating the need for using clinical laboratories and the necessity for patient recall. The most convenient fluid to monitor is the dialysate, which is the capturing medium for blood contaminants during the hemodialysis process. Monitoring in dialysate would result in a completely in vitro procedure. By use of an appropriate sensor arrangement, the dialysate could be continuously or intermittently monitored at the point-of-care. A further enhancement of this general principle is a home monitor, which would allow at-home testing to determine if dialysis was necessary. Such a home monitor could be similar, in principle, to devices used for blood glucose testing by diabetics. Such a device could require a mere blood droplet sample provided by a finger prick.
The above-referenced needs have been satisfied by the present invention which involves an electrochemical sensor whereby the dialysate can be continuously or intermittently monitored, and can be incorporated into a home monitor. The sensing element is used with an appropriate electronics package and can be tied to a computerized system which would contain individual patient case histories, to determine the dialysis end points. The sensor of this invention is based upon measurement of the pH change produced in an aqueous environment by the products of the enzyme-catalyzed hydrolysis of urea. The sensor element consists of a solid-state pH-sensitive material, such as IrO.sub.2, coated with the enzyme urease.